bims-hafaim 2023-01-15 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023‒01‒15
seven papers selected by
Kyle McCommis
Saint Louis University

Dietary essential amino acids for the treatment of heart failure with reduced ejection fraction.
SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism.
Impaired insulin-stimulated myocardial glucose metabolic rate is associated with reduced estimated myocardial energetic efficiency in subjects with different degrees of glucose tolerance.
Low-Intensity Exercise Affects Cardiac Fatty Acid Oxidation by Increasing the Nuclear Content of PPARα, FOXO1, and Lipin1 in Fructose-Fed Rats.
Empagliflozin inhibits excessive autophagy through the AMPK/GSK3β signaling pathway in diabetic cardiomyopathy.
Quantification and Proteomic Characterization of β-hydroxybutyrylation Modification in the Hearts of AMPKα2 Knockout Mice.
Deficiency of Adipose Triglyceride Lipase Induces Metabolic Syndrome and Cardiomyopathy in Zebrafish.

Cardiovasc Res. 2023 Jan 10. pii: cvad005. [Epub ahead of print]

Dietary essential amino acids for the treatment of heart failure with reduced ejection fraction.

Maurizio Ragni, Carolina Magdalen Greco, Arianna Felicetta, Shuxun Vincent Ren, Paolo Kunderfranco, Chiara Ruocco, Pierluigi Carullo, Veronica Larcher, Laura Tedesco, Ilenia Severi, Antonio Giordano, Saverio Cinti, Alessandra Valerio, Haipeng Sun, Yibin Wang, Chen Gao, Gianluigi Condorelli, Enzo Nisoli.

  AIMS: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of mortality worldwide, requiring novel therapeutic and lifestyle interventions. Metabolic alterations and energy production deficit are hallmarks and thereby promising therapeutic targets for this complex clinical syndrome. We aim to study the molecular mechanisms and effects on cardiac function in rodents with HFrEF of a designer diet in which free essential amino acids - in specifically designed percentages - substituted for protein.METHODS AND RESULTS: Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricle (LV) pressure overload or sham surgery. Whole body glucose homeostasis was studied with glucose tolerance test, while myocardial dysfunction and fibrosis were measured with echocardiogram and histological analysis. Mitochondrial bioenergetics and morphology were investigated with oxygen consumption rate measurement and electron microscopy evaluation. Circulating and cardiac non-targeted metabolite profiles were analyzed by ultrahigh performance liquid chromatography-tandem mass spectroscopy, while RNA sequencing was used to identify signalling pathways mainly affected. The amino acid-substituted diet shows remarkable preventive and therapeutic effects. This dietary approach corrects the whole-body glucose metabolism and restores the unbalanced metabolic substrate usage - by improving mitochondrial fuel oxidation - in the failing heart. In particular, biochemical, molecular, and genetic approaches suggest that renormalization of branched-chain amino acid oxidation in cardiac tissue, which is suppressed in HFrEF, plays a relevant role. Beyond the changes of systemic metabolism, cell-autonomous processes may explain at least in part the diet's cardioprotective impact.
CONCLUSION: Collectively, these results suggest that manipulation of dietary amino acids, and especially essential amino acids, is a potential adjuvant therapeutic strategy to treat systolic dysfunction and HFrEF in humans.

Keywords:  amino acids; heart failure; mitochondrial function; nutrition; transcriptomic reprogramming

DOI:  https://doi.org/10.1093/cvr/cvad005
Nat Rev Cardiol. 2023 Jan 06.

SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism.

Milton Packer.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.

DOI: https://doi.org/10.1038/s41569-022-00824-4
Cardiovasc Diabetol. 2023 Jan 09. 22(1): 4

Impaired insulin-stimulated myocardial glucose metabolic rate is associated with reduced estimated myocardial energetic efficiency in subjects with different degrees of glucose tolerance.

Elena Succurro, Francesco Cicone, Annalisa Papa, Sofia Miceli, Patrizia Vizza, Teresa Vanessa Fiorentino, Maria Perticone, Angela Sciacqua, Pietro Hiram Guzzi, Pierangelo Veltri, Giuseppe Lucio Cascini, Francesco Andreozzi, Giorgio Sesti.

  BACKGROUND: Alterations in myocardial mechano-energetic efficiency (MEEi), which represents the capability of the left ventricles to convert the chemical energy obtained by oxidative metabolism into mechanical work, have been associated with cardiovascular disease. Although whole-body insulin resistance has been related to impaired myocardial MEEi, it is unknown the relationship between cardiac insulin resistance and MEEi. Aim of this study was to evaluate the relationship between insulin-stimulated myocardial glucose metabolic rate (MrGlu) and myocardial MEEi in subjects having different degrees of glucose tolerance.METHODS: We evaluated insulin-stimulated myocardial MrGlu using cardiac dynamic positron emission tomography (PET) with 18F-Fluorodeoxyglucose (18F-FDG) combined with euglycemic-hyperinsulinemic clamp, and myocardial MEEi in 57 individuals without history of coronary heart disease having different degrees of glucose tolerance. The subjects were stratified into tertiles according to their myocardial MrGlu values.
RESULTS: After adjusting for age, gender and BMI, subjects in I tertile showed a decrease in myocardial MEEi (0.31 ± 0.05 vs 0.42 ± 0.14 ml/s*g, P = 0.02), and an increase in myocardial oxygen consumption (MVO2) (10,153 ± 1375 vs 7816 ± 1229 mmHg*bpm, P < 0.0001) as compared with subjects in III tertile. Univariate correlations showed that insulin-stimulated myocardial MrGlu was positively correlated with MEEi and whole-body glucose disposal, and negatively correlated with waist circumference, fasting plasma glucose, HbA1c and MVO2. In a multivariate regression analysis running a model including several CV risk factors, the only variable that remained significantly associated with MEEi was myocardial MrGlu (β 0.346; P = 0.01).
CONCLUSIONS: These data suggest that an impairment in insulin-stimulated myocardial glucose metabolism is an independent contributor of depressed myocardial MEEi in subjects without history of CHD.

Keywords:  Cardiac 18F-FDG PET; Cardiac workload; Cardiovascular disease; Insulin sensitivity; Myocardial glucose metabolism; Myocardial mechano-energetic efficiency; Prediabetes; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12933-022-01733-z
Metab Syndr Relat Disord. 2023 Jan 10.

Low-Intensity Exercise Affects Cardiac Fatty Acid Oxidation by Increasing the Nuclear Content of PPARα, FOXO1, and Lipin1 in Fructose-Fed Rats.

Milan Kostić, Goran Korićanac, Snežana Tepavčević, Jelena Stanišić, Snježana Romić, Tijana Ćulafić, Tamara Ivković, Mojca Stojiljković.

  Background and Aim: Excessive fructose consumption along with a sedentary lifestyle provokes metabolic disorders and cardiovascular diseases. Fructose overload causes cardiac insulin resistance and increases reliance on fatty acid (FA) uptake and catabolism. The cardiometabolic benefits of exercise training have long been appreciated. The goal of the presented study is to shed a new light to the preventive role of exercise training on cardiac lipid metabolism in fructose-fed rats. Methods: Male Wistar rats were divided into control (C), sedentary fructose (F), and exercised fructose (EF) groups. Fructose was given as a 10% fructose solution in drinking water for 9 weeks. Low-intensity exercise training was applied for 9 weeks. The protein expression and subcellular localization of Lipin1, peroxisome proliferator-activated receptor α (PPARα), and peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC1) were analyzed in the heart using Western blot. Cardiac forkhead box transcription factor 1 (FOXO1) and sirtuin 1 (SIRT1) protein levels were also evaluated. Gene expression of long-chain acyl-CoA dehydrogenase was analyzed by quantitative polymerase chain reaction. Results: Exercise training has augmented the expression of main regulators of FA oxidation in the heart and achieves its effect by increasing the nuclear content of PPARα, Lipin1, and FOXO1 compared with the fructose group (P = 0.0422, P = 0.000045, P = 0.00958, respectively). In addition, Lipin1, FOXO1, and SIRT1 were increased in nuclear extract after exercise compared with the control group (P = 0.000043, P = 0.0417, P = 0.0329, respectively). In cardiac lysate, low-intensity exercise caused significantly increased protein level of PPARα, PGC1, FOXO1, and SIRT1 compared with control (P = 0.0377, P = 0.0275, P = 0.0096, P = 0.0282, respectively) and PGC1 level compared with the fructose group (P = 0.0417). Conclusion: The obtained results imply that the heart with a metabolic burden additionally relies on FA as an energy substrate after low-intensity running.

Keywords:  FOXO1; PPARα; exercise; fatty acid oxidation; fructose-rich diet; heart

DOI:  https://doi.org/10.1089/met.2022.0078
Cardiovasc Res. 2023 Jan 11. pii: cvad009. [Epub ahead of print]

Empagliflozin inhibits excessive autophagy through the AMPK/GSK3β signaling pathway in diabetic cardiomyopathy.

Rosalinda Madonna, Stefania Moscato, Maria Concetta Cufaro, Damiana Pieragostino, Letizia Mattii, Piero Del Boccio, Sandra Ghelardoni, Riccardo Zucchi, Raffaele De Caterina.

  BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on heart failure and cardiovascular mortality in diabetic and nondiabetic patients, with unclear mechanisms. Autophagy is a cardioprotective mechanism under acute stress conditions, but excessive autophagy accelerates myocardial cell death leading to autosis. We evaluated the protective role of empagliflozin (EMPA) against cardiac injury in murine diabetic cardiomyopathy.METHODS AND RESULTS: Male mice, rendered diabetics by one single intraperitoneal injection of streptozotocin and treated with EMPA (30 mg/kg/day) had fewer apoptotic cells (4.9 ± 2.1 vs 1 ± 0.5 TUNEL-positive cells %, p < 0.05), less senescence (10.1 ± 2 vs 7.9 ± 1.2 β-gal positivity/tissue area, p < 0.05), fibrosis (0.2 ± 0.05 vs 0.15 ± 0.06, p < 0.05 fibrotic area/tissue area), autophagy (7.9 ± 0.05 vs 2.3 ± 0.6 fluorescence intensity/total area, p < 0.01), and connexin (Cx)-43 lateralization compared with diabetic mice. Proteomic analysis showed a downregulation of the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway and upstream activation of sirtuins in the heart of diabetic mice treated with EMPA compared with diabetic mice. Because sirtuin activation leads to modulation of cardiomyogenic transcription factors, we analyzed the DNA binding activity to serum response elements (SRE) of serum response factor (SRF) by electromobility shift assay. Compared with diabetic mice (0.5 ± 0.01 densitometric units, DU), nondiabetic mice treated with EMPA (2.2 ± 0.01 DU, p < 0.01) and diabetic mice treated with EMPA (2.0 ± 0.1 DU, p < 0.01) significantly increased SRF binding activity to SRE, paralleled by increased cardiac actin expression (4.1 ± 0.1 vs 2.2 ± 0.01 target protein/β-actin ratio, p < 0.01). EMPA significantly reversed cardiac dysfunction on echocardiography in diabetic mice and inhibited excessive autophagy in high-glucose-treated cardiomyocytes by inhibiting the autophagy inducer GSK3β, leading to reactivation of cardiomyogenic transcription factors.
CONCLUSIONS: Taken together, our results describe a novel paradigm in which EMPA inhibits hyperactivation of autophagy through the AMPK/GSK3β signaling pathway in the context of diabetes.

Keywords:  autophagy; connexins; diabetic cardiomyopathy; empagliflozin; glycogen synthase kinase 3 beta; serum response factor; sodium-glucose cotransporter type 2 (SGLT2) inhibitors

DOI:  https://doi.org/10.1093/cvr/cvad009
Mol Cell Proteomics. 2023 Jan 05. pii: S1535-9476(23)00003-8. [Epub ahead of print] 100494

Quantification and Proteomic Characterization of β-hydroxybutyrylation Modification in the Hearts of AMPKα2 Knockout Mice.

Wen-Jing Ding, Xue-Hui Li, Cong-Min Tang, Xue-Chun Yang, Yan Sun, Yi-Ping Song, Ming-Ying Ling, Rong Yan, Hai-Qing Gao, Wen-Hua Zhang, Na Yu, Jun-Chao Feng, Zhen Zhang, Yan-Qiu Xing.

  AMP-activated protein kinase alpha 2 (AMPKα2) regulates energy metabolism, protein synthesis, and glucolipid metabolism myocardial cells. Ketone bodies (KB) produced by fatty acid β-oxidation, especially β-hydroxybutyrate (β-OHB), are fatty energy-supplying substances for the heart, brain, and other organs during fasting and long-term exercise. They also regulate metabolic signaling for multiple cellular functions. Lysine β-hydroxybutyrylation (Kbhb) is a β-OHB mediated protein post-translational modification (PTMs). Histone Kbhb has been identified in yeast, mouse, and human cells. However, whether AMPK regulates protein Kbhb is yet unclear. Hence, the present study explored the changes in proteomics and Kbhb modification omics in the hearts of AMPKα2 knockout mice using a comprehensive quantitative proteomic analysis. Based on mass spectrometry (LC-MS/MS) analysis, the number of 1181 Kbhb modified sites in 455 proteins were quantified between AMPKα2 knockout (AK) mice and wild-type (WT) mice; 244 Kbhb sites in 142 proteins decreased or increased after AMPKα2 knockout (fold change >1.5 or <1/1.5, P＜0.05). The regulation of Kbhb sites in 26 key enzymes of fatty acid degradation and tricarboxylic acid cycle (TCA cycle) was noted in AMPKα2 knockout mouse cardiomyocytes. These findings, for the first time, identified proteomic features and Kbhb modification of cardiomyocytes after AMPKα2 knockout, suggesting that AMPKα2 regulates energy metabolism by modifying protein Kbhb.

Keywords:  AMPKα2; TCA cycle; fatty acid degradation; heart; proteomics; β-hydroxybutyrylation

DOI:  https://doi.org/10.1016/j.mcpro.2023.100494
Int J Mol Sci. 2022 Dec 21. pii: 117. [Epub ahead of print]24(1):

Deficiency of Adipose Triglyceride Lipase Induces Metabolic Syndrome and Cardiomyopathy in Zebrafish.

Hsin-Hung Lai, Kun-Yun Yeh, Hung-Ming Hsu, Guor Mour Her.

  Lipid metabolism dysfunction is related to clinical disorders including obesity, cancer, liver steatosis, and cardiomyopathy. Impaired lipolytic enzymes result in altered release of free fatty acids. The dramatic change in dyslipidemia is important in lipotoxic cardiomyopathy. Adipose triglyceride lipase (ATGL) catalyzes the lipolysis of triacylglycerol to reduce intramyocardial triglyceride levels in the heart and improve myocardial function. We examined the role of ATGL in metabolic cardiomyopathy by developing an Atgl knockout (ALKO) zebrafish model of metabolic cardiomyopathy disease by continuously expressing CRISPR/Cas9 protein and atgl gene guide RNAs (gRNAs). The expressed Cas9 protein bound to four gRNAs targeting the atgl gene locus, facilitating systemic gene KO. Ablation of Atgl interfered with lipid metabolism, which induced hyperlipidemia and hyperglycemia. ALKO adults and embryos displayed hypertrophic hearts. ALKO presented a typical dilated cardiomyopathy profile with a remarkable reduction in four sarcomere genes (myosin heavy chain 7-like, actin alpha cardiac muscle 1b, myosin binding protein C3, and troponin T type 2a) and two Ca2+ handling regulator genes (tropomyosin 4b and ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2b). Immune cell infiltration in cardiac tissue of ALKO provided direct evidence of advanced metabolic cardiomyopathy. The presently described model could become a powerful tool to clarify the underlying mechanism between metabolic disorders and cardiomyopathies.

Keywords:  cardiomyopathy; lipid metabolism; lipolysis; metabolic syndrome

DOI:  https://doi.org/10.3390/ijms24010117